EP2509945B1 - 4-(azacycloalkyl)-benzene-1,3-diol derivatives as tyrosinase inhibitors and their synthesis and use thereof - Google Patents
4-(azacycloalkyl)-benzene-1,3-diol derivatives as tyrosinase inhibitors and their synthesis and use thereof Download PDFInfo
- Publication number
- EP2509945B1 EP2509945B1 EP10787772.2A EP10787772A EP2509945B1 EP 2509945 B1 EP2509945 B1 EP 2509945B1 EP 10787772 A EP10787772 A EP 10787772A EP 2509945 B1 EP2509945 B1 EP 2509945B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- diol
- benzene
- radical
- sulphonyl
- piperidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 *c(c(OCc1ccccc1)c1)cc(*)c1OCc1ccccc1 Chemical compound *c(c(OCc1ccccc1)c1)cc(*)c1OCc1ccccc1 0.000 description 6
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/96—Sulfur atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur atoms
Definitions
- the invention relates to novel 4-(azacycloalkyl)-benzene-1,3-diol compounds as industrial and consumer products. It also relates to a method for their preparation and to their use, as tyrosinase inhibitors, in pharmaceutical or cosmetic compositions for the treatment or prevention of pigmentary disorders.
- Pigmentation of the skin results from the synthesis of melanin by dendritic cells known as melanocytes.
- Melanocytes contain organelles known as melanosomes which transfer melanin into the upper keratinocyte layers which are then transported to the surface of the skin by differentiation of the epidermis ( Gilchrest B A, Park H Y, Eller M S, Yaar M, Mechanisms of ultraviolet light-induced pigmentation. Photochem Photobiol 1996; 63: 1-10 ; Hearing V J, Tsukamoto K, Enzymatic control of pigmentation in mammals. FASEB J 1991; 5: 2902-2909 ).
- Tyrosinase is a key enzyme among melanogenesis enzymes which catalyses the first two steps of melanin synthesis. Homozygotic mutations of tyrosinase cause oculocutaneous albinism type I, characterized by a complete absence of melanin synthesis ( Toyofuku K, Wada I, Spritz R A, Hearing V J, The molecular basis of oculocutaneous albinism type 1 (OCA1) : sorting failure and degradation of mutant tyrosinases results in a lack of pigmentation. Biochem J 2001; 355: 259-269 ).
- the majority of known skin lightening compounds are phenols or hydroquinone derivatives. Those compounds inhibit tyrosinase, but the majority of them are cytotoxic as regards melanocytes. This toxic effect risks causing permanent depigmentation of the skin. Producing compounds that could inhibit melanogenesis while remaining low in cytotoxicity or devoid of toxicity as regards melanocytes would be of particular interest.
- patent application WO99/15148 discloses the use of 4-cycloalkylresorcinols as a depigmentation agent.
- Patent FR 2 704 428 discloses the use of 4-haloresorcinols as depigmentation agents.
- Patent applications WO2006/097224 and WO2006/097223 disclose the use of 4-cycloalkylmethylresorcinols as depigmentation agents.
- Patent application WO2005/085169 discloses the use of alkyl 3-(2,4-dihydroxyphenyl)propionates as depigmentation agents.
- Patent application WO2004/017936 discloses the use of 3-(2,4-dihydroxyphenyl)acrylamide as a depigmentation agent.
- Patent application WO2004/052330 discloses the use of 4-[1,3]dithian-2-ylresorcinols as depigmentation agents.
- WO 02/20474 discloses the use of 4-cycloalkylresorcinols as skin lightening agents.
- patent EP 0 341 664 discloses the use of 4-alkylresorcinols as depigmentation agents, among them 4-n-butyl resorcinol, also known as Rucinol, which forms part of the composition of a depigmentation cream sold under the trade name Iklen®.
- novel compounds with a 4-(azacycloalkyl)benzene-1,3-diol structure have very good tyrosinase enzyme inhibiting activity and very low cytotoxicity. Furthermore, these compounds have a tyrosinase enzyme inhibiting activity which is greater than that of Rucinol while being less cytotoxic as regards melanocytes than Rucinol.
- These compounds may have applications in human medicine, especially in dermatology and in the cosmetics field.
- Preferred salts of the compounds with general formula (I) with a pharmaceutically acceptable base which may be cited are salts with an organic base or with an inorganic base.
- suitable inorganic bases are potassium hydroxide, sodium hydroxide or calcium hydroxide.
- Suitable organic bases are morpholine, piperazine and lysine.
- the compounds with general formula (I) may also exist in hydrated or solvated forms.
- Suitable solvents for forming solvates are alcohols such as ethanol or isopropanol.
- C1-C8 alkyl denotes a saturated linear or branched hydrocarbon chain containing 1 to 8 carbon atoms.
- C3-C8 cycloalkyl denotes a saturated cyclic hydrocarbon chain containing 3 to 8 carbon atoms.
- C4-C10 methylcycloalkyl denotes methyl substituted with a saturated, cyclic or bicyclic hydrocarbon chain containing 3 to 9 carbon atoms, which may be substituted with an oxygen atom.
- aryl means a phenyl or a naphthyl group.
- substituted aryl means a phenyl or a naphthyl group substituted with one or more groups of atoms selected from a C1-C8 alkyl, a C1-C5 alkoxy, a halogen and a trifluoromethyl group.
- heteroaryl means a pyridine or a quinoline group.
- substituted heteroaryl means a pyridine or a quinoline group substituted with one or more groups of atoms selected from a C1-C8 alkyl, a C1-C5 alkoxy, a halogen and a trifluoromethyl group.
- Preferred possible substitutions on a phenyl, a naphthyl, a pyridine or a quinoline group are those where said radicals are substituted with methyl (C1 alkyl).
- aralkyl denotes a C1-C8 alkyl radical as defined above and substituted with a substituted or unsubstituted aryl radical.
- C1-C5 alkoxy denotes an oxygen atom substituted with a linear or branched saturated hydrocarbon chain containing 1 to 5 carbon atoms.
- halogen denotes a chlorine, fluorine, bromine or iodine atom.
- R1 represents:
- the compounds with general formula (I) are prepared using the general reaction scheme shown in Figure 1 .
- the compounds with general formula (4) are obtained by hydrogenation of benzyl alcohols with general formula (3) in the presence of hydrogen and a palladium-based catalyst such as palladium on charcoal, for example in a solvent such as methanol ( Merschaert A; Delhaye L; Ketesmont J-P; Brione W; Delbeke P; Mancuso V; Napora F; Diker K; Giraud D; Vanmarsenille M; Tetrahedron Lett 2003, 44 (24), 4531-4534 ).
- a solvent such as methanol
- the compounds with general formula (4) are transformed into amines with general formula (5) by the action of trifluoroacetic acid in a solvent such as dichloromethane, for example ( Kasyan A; Wagner C; Maier M E; Tetrahedron 1998, 54 (28), 8047-8054 ) or by the action of hydrogen chloride in solution in ethyl acetate, for example.
- a solvent such as dichloromethane, for example ( Kasyan A; Wagner C; Maier M E; Tetrahedron 1998, 54 (28), 8047-8054 ) or by the action of hydrogen chloride in solution in ethyl acetate, for example.
- the compounds with general formula (5) are then transformed into compounds with general formula (I) by reaction with a derivative comprising a chlorosulphonyl function, for example in a solvent such as DMF in the presence of a base such as diisopropylamine, for example.
- the invention thus envisages at least a compound of formula (I) for use as a drug.
- the invention also envisages at least one compound with general formula (I) as hereinbefore defined for use, as a drug, in which said compound has a tyrosinase inhibiting activity.
- the invention also envisages the use of at least one compound with general formula (I) as hereinbefore defined for the preparation of a pharmaceutical or cosmetic composition in which said compound has a tyrosinase inhibiting activity.
- the compounds of the present invention have an IC50 value (dose inhibiting 50% of enzymatic activity) towards tyrosinase of 10 ⁇ M or less, more particularly 1 ⁇ M or less.
- the invention also concerns a compound with general formula (I) for its use in the treatment and/or prevention of pigmentary disorders.
- the compounds with general formula (I) of the invention are particularly suitable for use connected with the treatment and/or prevention of pigmentary disorders such as melasma, chloasma, lentigines, senile lentigo, irregular hyperpigmentations linked to photo-ageing, freckles, post-inflammatory hyperpigmentations due to abrasion, a burn, a scar, dermatosis, a contact allergy; naevi, hyperpigmentations with genetic determinism, hyperpigmentations of metabolic or drug origin, melanomas or any other hyperpigmentary lesion.
- pigmentary disorders such as melasma, chloasma, lentigines, senile lentigo, irregular hyperpigmentations linked to photo-ageing, freckles, post-inflammatory hyperpigmentations due to abrasion, a burn, a scar, dermatosis, a contact allergy; naevi, hyperpigmentations with genetic determinism, hyper
- the present invention also pertains to a pharmaceutical composition in particular for the treatment of the disorders cited above, which is characterized in that it comprises, in a pharmaceutically acceptable support which is compatible with the mode of administration used therewith, a compound with general formula (I) in one of its isomeric or enantiomeric forms, or one of its salts with a pharmaceutically acceptable base.
- pharmaceutically acceptable support means a medium which is compatible with the skin, mucosae, hair and nails.
- composition of the invention may be administered topically.
- the pharmaceutical composition is packaged in a form which is suitable for topical application.
- topical application means that the pharmaceutical composition of the invention is more particularly intended for the treatment of the skin and the mucosae and may be in the form of a liquid, paste or solid, more particularly in the form of ointments, creams, solutions or gels.
- compositions used for topical application have a concentration of the compound of the invention which is generally in the range 0.001% to 10% by weight, preferably in the range 0.01% to 5% by weight with respect to the total composition weight.
- the compounds with general formula (I) of the invention also have an application in the cosmetic field, in particular in protection against the deleterious effect of the sun, in order to prevent and/or combat photo-induced or chronological ageing of the skin, and also to lighten skins with a dark phototype.
- composition comprising at least one of the compounds with formula (I), in a cosmetically acceptable support.
- cosmetically acceptable medium means a medium which is compatible with the skin, mucosae, hair and nails.
- the invention also pertains to the cosmetic use of a composition comprising at least one compound with general formula (I), to prevent and/or treat signs of ageing and/or the skin.
- the invention also pertains to the cosmetic use of a composition comprising at least one compound with general formula (I) for body or hair care.
- the cosmetic composition of the invention containing a compound with general formula (I) or one of its isomeric or enantiomeric forms or one of its salts with a cosmetically acceptable base in a cosmetically acceptable support may be in the form of a cream, a milk, a gel, suspensions of microspheres or nanospheres or lipid or polymeric vesicles, impregnated pads, solutions, sprays, foams, sticks, soaps, wash bases or shampoos.
- the concentration of the compound with general formula (I) in the cosmetic composition is preferably in the range 0.001% to 10% by weight with respect to the total composition weight.
- compositions as described above may also contain inert additives or even pharmacological active ingredients in the pharmaceutical compositions, or combinations of such additives, and in particular:
- the activity of the inhibitors was measured using a lysate of B16F1 cells (murine melanoma line).
- B16F1 cells murine melanoma line.
- the tyrosinase present in these cells catalyses the hydroxylation of L-tyrosine to L-DOPA then oxidation of the L-DOPA to dopaquinone.
- MBTH 3-methyl-2-benzothiazolinone hydrazone
- dopaquinone is trapped to form a pink complex which absorbs at 520 nm.
- the B16F1 cells were cultivated in DMEM medium + 10% foetal calf serum + 10 -9 M of ⁇ MSH for 4 days at 37°C under 7% CO 2 . They were treated with trypsin, washed with PBS, counted and centrifuged. The pellet was taken up in an amount of 10 7 cells/mL in lysis buffer (sodium phosphate, 10 mM pH 6.8 - Igepal 1%) and the suspension was treated with ultrasound for 10 seconds. After centrifuging for 30 minutes at 4000 rpm, the supernatant obtained constituted the cell lysate used as the source of tyrosinase in the enzymatic test.
- the plate was incubated at 37°C and a spectrographic recording was produced at 520 nm after 6 hours incubation. In order to compensate for any absorption by the products, a corrected absorbance was used (absorbance at time 6 h - absorbance at time zero).
- the inhibitors were dose-response tested in order to calculate the IC50 (dose inhibiting 50% of enzymatic activity).
- Table A Table A Name Structure Tyrosine hydroxylase/ Dopa oxidase IC50 ( ⁇ M) 4-butylresorcinol (Rucinol) 3 Compound 2 1.5
- the inhibition of melanogenesis was measured in MNT1 human melanoma cells using a protocol adapted from Reigner et al, Cell Mol Biol (1999) 45: 969-980 .
- the test was based on the concomitant incorporation of 2 radiolabelled tracers: 14 C-thiouracil is incorporated into neosynthesized melanin and reflects melanogenesis, while 3 H-leucine is incorporated into proteins and reflects cell viability and, as a result, the toxicity of the test compounds.
- the MNT1 cells were plated into 96-well plates in the presence of the test compounds and radioisotopes. After 24h incubation at 37°C, the cells were washed and the quantity of the 2 radioisotopes was measured.
- the test compounds were dose-response tested in order to calculate the IC50 inhibition of melanogenesis on the basis of the 14 C incorporation which was normalized by the 3 H incorporation. A cell toxicity IC50 was also calculated on the basis of the 3 H incorporation.
- This example illustrates various formulations based on the compounds of the invention.
Description
- The invention relates to novel 4-(azacycloalkyl)-benzene-1,3-diol compounds as industrial and consumer products. It also relates to a method for their preparation and to their use, as tyrosinase inhibitors, in pharmaceutical or cosmetic compositions for the treatment or prevention of pigmentary disorders.
- Pigmentation of the skin, especially human skin, results from the synthesis of melanin by dendritic cells known as melanocytes. Melanocytes contain organelles known as melanosomes which transfer melanin into the upper keratinocyte layers which are then transported to the surface of the skin by differentiation of the epidermis (Gilchrest B A, Park H Y, Eller M S, Yaar M, Mechanisms of ultraviolet light-induced pigmentation. Photochem Photobiol 1996; 63: 1-10; Hearing V J, Tsukamoto K, Enzymatic control of pigmentation in mammals. FASEB J 1991; 5: 2902-2909).
- Tyrosinase is a key enzyme among melanogenesis enzymes which catalyses the first two steps of melanin synthesis. Homozygotic mutations of tyrosinase cause oculocutaneous albinism type I, characterized by a complete absence of melanin synthesis (Toyofuku K, Wada I, Spritz R A, Hearing V J, The molecular basis of oculocutaneous albinism type 1 (OCA1) : sorting failure and degradation of mutant tyrosinases results in a lack of pigmentation. Biochem J 2001; 355: 259-269).
- In order to treat pigmentation disorders resulting from an increase in melanin production for which no treatment exists that satisfies all of the expectations of patients and dermatologists alike, the development of novel therapeutic approaches has proved to be important.
- The majority of known skin lightening compounds are phenols or hydroquinone derivatives. Those compounds inhibit tyrosinase, but the majority of them are cytotoxic as regards melanocytes. This toxic effect risks causing permanent depigmentation of the skin. Producing compounds that could inhibit melanogenesis while remaining low in cytotoxicity or devoid of toxicity as regards melanocytes would be of particular interest.
- Among the compounds which have been described in the literature, patent application
WO99/15148 -
Patent FR 2 704 428 - Patent applications
WO2006/097224 andWO2006/097223 disclose the use of 4-cycloalkylmethylresorcinols as depigmentation agents. - Patent application
WO2005/085169 discloses the use of alkyl 3-(2,4-dihydroxyphenyl)propionates as depigmentation agents. - Patent application
WO2004/017936 discloses the use of 3-(2,4-dihydroxyphenyl)acrylamide as a depigmentation agent. - Patent application
WO2004/052330 discloses the use of 4-[1,3]dithian-2-ylresorcinols as depigmentation agents. -
WO 02/20474 - More particularly, patent
EP 0 341 664 discloses the use of 4-alkylresorcinols as depigmentation agents, among them 4-n-butyl resorcinol, also known as Rucinol, which forms part of the composition of a depigmentation cream sold under the trade name Iklen®. - Surprisingly and unexpectedly, the Applicant has now discovered that novel compounds with a 4-(azacycloalkyl)benzene-1,3-diol structure have very good tyrosinase enzyme inhibiting activity and very low cytotoxicity. Furthermore, these compounds have a tyrosinase enzyme inhibiting activity which is greater than that of Rucinol while being less cytotoxic as regards melanocytes than Rucinol.
- These compounds may have applications in human medicine, especially in dermatology and in the cosmetics field.
-
- a C1-C8 alkyl radical;
- a C3-C8 cycloalkyl radical;
- a C4-C10 methylcycloalkyl radical;
- an aryl radical;
- a substituted aryl radical;
- a heteroaryl radical;
- a substituted heteroaryl radical;
- an aralkyl radical; or
- a C1-C5 alkoxy radical;
- Preferred salts of the compounds with general formula (I) with a pharmaceutically acceptable base which may be cited are salts with an organic base or with an inorganic base.
- Examples of suitable inorganic bases are potassium hydroxide, sodium hydroxide or calcium hydroxide.
- Examples of suitable organic bases are morpholine, piperazine and lysine.
- The compounds with general formula (I) may also exist in hydrated or solvated forms.
- Examples of suitable solvents for forming solvates are alcohols such as ethanol or isopropanol.
- According to the present invention, the term "C1-C8 alkyl" denotes a saturated linear or branched hydrocarbon chain containing 1 to 8 carbon atoms.
- According to the present invention, the term "C3-C8 cycloalkyl" denotes a saturated cyclic hydrocarbon chain containing 3 to 8 carbon atoms.
- According to the present invention, the term "C4-C10 methylcycloalkyl" denotes methyl substituted with a saturated, cyclic or bicyclic hydrocarbon chain containing 3 to 9 carbon atoms, which may be substituted with an oxygen atom.
- According to the present invention, the term "aryl" means a phenyl or a naphthyl group.
- According to the present invention, the term "substituted aryl" means a phenyl or a naphthyl group substituted with one or more groups of atoms selected from a C1-C8 alkyl, a C1-C5 alkoxy, a halogen and a trifluoromethyl group.
- According to the present invention, the term "heteroaryl" means a pyridine or a quinoline group.
- According to the present invention, the term "substituted heteroaryl" means a pyridine or a quinoline group substituted with one or more groups of atoms selected from a C1-C8 alkyl, a C1-C5 alkoxy, a halogen and a trifluoromethyl group.
- Preferred possible substitutions on a phenyl, a naphthyl, a pyridine or a quinoline group are those where said radicals are substituted with methyl (C1 alkyl).
- According to the present invention, the term "aralkyl" denotes a C1-C8 alkyl radical as defined above and substituted with a substituted or unsubstituted aryl radical.
- According to the present invention, the term "C1-C5 alkoxy" denotes an oxygen atom substituted with a linear or branched saturated hydrocarbon chain containing 1 to 5 carbon atoms.
- According to the present invention, the term "halogen" denotes a chlorine, fluorine, bromine or iodine atom.
- According to the present invention, particularly preferred compounds with general formula (I) are those wherein R1 represents:
- a substituted aryl radical;
- an aralkyl radical;
- a C3-C8 cycloalkyl radical; or
- a C4-C10 methylcycloalkyl radical;
- According to the present invention, more particularly preferred compounds with general formula (I) are those wherein R1 represents:
- a substituted aryl radical;
- an aralkyl radical;
- a C3-C8 cycloalkyl radical; or
- a C4-C10 methylcycloalkyl radical;
- Y represents hydrogen or fluorine; and
- m = 1 and n = 1;
- The following examples of compounds with formula (I) that fall within the scope of the present invention may in particular be cited:
- 1: 4-(1-phenylmethanesulphonylpiperidin-4-yl)-benzene-1,3-diol;
- 2: 4-[1-(toluene-4-sulphonyl)piperidin-4-yl]-benzene-1,3-diol;
- 3: 4-[1-(butane-1-sulphonyl)piperidin-4-yl]benzene-1,3-diol;
- 4: 4-(1-cyclohexylmethanesulphonylpiperidin-4-yl)-benzene-1,3-diol;
- 5: 4-[1-(2-phenylethanesulphonyl)piperidin-4-yl]-benzene-1,3-diol;
- 6: 1-[4-(2,4-dihydroxyphenyl)piperidine-1-sulphonylmethyl]-7,7-dimethyl-bicyclo[2.2.1]heptan-2-one;
- 7: 4-fluoro-6-[1-(toluene-4-sulphonyl)piperidin-4-yl]benzene-1,3-diol;
- 8: 4-fluoro-6-(1-phenylmethanesulphonylpiperidin-4-yl)benzene-1,3-diol;
- 9: 4-fluoro-6-[1-(2-phenylethanesulphonyl)piperidin-4-yl]benzene-1,3-diol;
- 10: 4-(1-cyclohexylmethanesulphonylpiperidin-4-yl)-6-fluorobenzene-1,3-diol;
- 11: 4-[1-(butane-1-sulphonyl)piperidin-4-yl]-6-fluorobenzene-1,3-diol;
- 12: 4-[1-(toluene-4-sulphonyl)pyrrolidin-3-yl]-benzene-1,3-diol;
- 13: 4-(1-phenylmethanesulphonylpyrrolidin-3-yl)-benzene-1,3-diol;
- 14: 4-[1-(2-phenylethanesulphonyl)pyrrolidin-3-yl]-benzene-1,3-diol;
- 15: 4-fluoro-6-[1-(2-phenylethanesulphonyl)-pyrrolidin-3-yl]benzene-1,3-diol;
- 16: 4-(1-cyclohexylmethanesulphonylpyrrolidin-3-yl)-benzene-1,3-diol;
- 17: 4-[1-(butane-1-sulphonyl)pyrrolidin-3-yl]-benzene-1,3-diol.
- The compounds with general formula (I) are prepared using the general reaction scheme shown in
Figure 1 . - The
compounds 2,4-bisbenzyloxybromobenzene (X=Br; Y=H) or 1,5-bisbenzyloxy-2-fluoro-4-iodobenzene (X=I; Y=F) (1), either commercially available or prepared using conventional synthesis methods (W D Langley, Org Synth I, 122 (1932) or, in the case of the fluorinated compounds: Mottram L F; Boonyarattanakalin S; Kovel R E; Peterson B R Organic Letters 2006, 8(4), 581-584), react in the presence of butyl lithium, for example with azacycloalkanones (2), commercially available or prepared using conventional synthesis methods (W D Langley, Org Synth I, 122 (1932)) to provide the corresponding benzyl alcohols with general formula (3) in which Y=H or F (Annoura H; Nakanishi K; Uesugi M; Fukunaga A; Imajo S; Miyajima A; Tamura-Horikawa Y; Tamura S; Bioorg Med Chem 2002, 10 (2), 371-383). - The compounds with general formula (4) are obtained by hydrogenation of benzyl alcohols with general formula (3) in the presence of hydrogen and a palladium-based catalyst such as palladium on charcoal, for example in a solvent such as methanol (Merschaert A; Delhaye L; Ketesmont J-P; Brione W; Delbeke P; Mancuso V; Napora F; Diker K; Giraud D; Vanmarsenille M; Tetrahedron Lett 2003, 44 (24), 4531-4534).
- The compounds with general formula (4) are transformed into amines with general formula (5) by the action of trifluoroacetic acid in a solvent such as dichloromethane, for example (Kasyan A; Wagner C; Maier M E; Tetrahedron 1998, 54 (28), 8047-8054) or by the action of hydrogen chloride in solution in ethyl acetate, for example.
-
- The invention thus envisages at least a compound of formula (I) for use as a drug.
- The invention also envisages at least one compound with general formula (I) as hereinbefore defined for use, as a drug, in which said compound has a tyrosinase inhibiting activity.
- The invention also envisages the use of at least one compound with general formula (I) as hereinbefore defined for the preparation of a pharmaceutical or cosmetic composition in which said compound has a tyrosinase inhibiting activity.
- Advantageously, the compounds of the present invention have an IC50 value (dose inhibiting 50% of enzymatic activity) towards tyrosinase of 10 µM or less, more particularly 1 µM or less.
- The invention also concerns a compound with general formula (I) for its use in the treatment and/or prevention of pigmentary disorders.
- The compounds with general formula (I) of the invention are particularly suitable for use connected with the treatment and/or prevention of pigmentary disorders such as melasma, chloasma, lentigines, senile lentigo, irregular hyperpigmentations linked to photo-ageing, freckles, post-inflammatory hyperpigmentations due to abrasion, a burn, a scar, dermatosis, a contact allergy; naevi, hyperpigmentations with genetic determinism, hyperpigmentations of metabolic or drug origin, melanomas or any other hyperpigmentary lesion.
- The present invention also pertains to a pharmaceutical composition in particular for the treatment of the disorders cited above, which is characterized in that it comprises, in a pharmaceutically acceptable support which is compatible with the mode of administration used therewith, a compound with general formula (I) in one of its isomeric or enantiomeric forms, or one of its salts with a pharmaceutically acceptable base.
- The term "pharmaceutically acceptable support" means a medium which is compatible with the skin, mucosae, hair and nails.
- The composition of the invention may be administered topically. Preferably, the pharmaceutical composition is packaged in a form which is suitable for topical application.
- The term "topical application" means that the pharmaceutical composition of the invention is more particularly intended for the treatment of the skin and the mucosae and may be in the form of a liquid, paste or solid, more particularly in the form of ointments, creams, solutions or gels.
- The compositions used for topical application have a concentration of the compound of the invention which is generally in the range 0.001% to 10% by weight, preferably in the range 0.01% to 5% by weight with respect to the total composition weight.
- The compounds with general formula (I) of the invention also have an application in the cosmetic field, in particular in protection against the deleterious effect of the sun, in order to prevent and/or combat photo-induced or chronological ageing of the skin, and also to lighten skins with a dark phototype.
- The invention thus also pertains to a composition comprising at least one of the compounds with formula (I), in a cosmetically acceptable support. The term "cosmetically acceptable medium" means a medium which is compatible with the skin, mucosae, hair and nails.
- The invention also pertains to the cosmetic use of a composition comprising at least one compound with general formula (I), to prevent and/or treat signs of ageing and/or the skin.
- The invention also pertains to the cosmetic use of a composition comprising at least one compound with general formula (I) for body or hair care.
- The cosmetic composition of the invention containing a compound with general formula (I) or one of its isomeric or enantiomeric forms or one of its salts with a cosmetically acceptable base in a cosmetically acceptable support may be in the form of a cream, a milk, a gel, suspensions of microspheres or nanospheres or lipid or polymeric vesicles, impregnated pads, solutions, sprays, foams, sticks, soaps, wash bases or shampoos.
- The concentration of the compound with general formula (I) in the cosmetic composition is preferably in the range 0.001% to 10% by weight with respect to the total composition weight.
- The pharmaceutical and cosmetic compositions as described above may also contain inert additives or even pharmacological active ingredients in the pharmaceutical compositions, or combinations of such additives, and in particular:
- wetting agents;
- taste improving agents;
- preservatives, such as parahydroxybenzoic acid esters;
- stabilizing agents;
- moisture regulating agents;
- pH regulating agents;
- osmotic pressure modifying agents;
- emulsifying agents;
- UV-A and UV-B screens;
- antioxidants such as α-tocopherol, butylhydroxyanisole or butylhydroxytoluene, superoxide dismutase, or ubiquinol; sodium metabisulphite;
- emollients;
- moisturizers such as glycerol, PEG 400, thiamorpholinone and its derivatives, or urea;
- antiseborrheic or antiacne agents such as S-carboxymethylcysteine, S-benzylcysteamine, their salts or derivatives, or benzoyl peroxide.
- Clearly, the skilled person will take care to select any compounds to be added to said compositions so that the advantageous properties intrinsically associated with the present invention are not or are not substantially altered by the envisaged addition.
- Some examples will now be given by way of entirely non-limiting illustration of the production of compounds with general formula (I) of the invention, the biological activity results for these compounds and various formulations based on such compounds.
- 107 g (0.771 mol, 3 eq) of potassium carbonate (325 mesh) was added to a solution of 50.1 g (0.257 mol, 1 eq) of 97% 4-bromoresorcinol in 500 mL of acetone. The reaction medium was cooled to 5-10°C and 75 mL (0.630 mol, 2.45 eq) of benzyl bromide was added dropwise. The reaction medium was stirred at ambient temperature overnight then heated to 50 °C for 2 hours. The solvent was evaporated off then the residue was taken up in a water-ethyl acetate mixture. The aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with a saturated sodium chloride solution, dried over magnesium sulphate, filtered and evaporated. The residue (114 g) was chromatographed on silica gel (600 g), eluting with 90/10 heptane/dichloromethane.
- 94.4 g of 2,4-bisbenzyloxy-1-bromobenzene was obtained in the form of white crystals. Yield = 99%.
- 2 mL (5 mmol, 1.2 eq) of 2.5 M n-butyl lithium in hexane was added to a solution of 1.55 g (4 mmol, 1 eq) of 2,4-bisbenzyloxy-1-bromobenzene in 15 mL of methyltetrahydrofuran cooled to -70°C. The reaction medium was stirred at -70°C for 25 minutes and 1.0 g (5 mmol, 1.2 eq) of 1-boc-4-piperidone in solution in 10 mL of methyltetrahydrofuran was added. The reaction medium was stirred at -70°C for 1 hour then left overnight to come up to ambient temperature. 15 mL of a saturated solution of ammonium chloride supplemented with 2 mL of 2N hydrochloric acid was added to the reaction medium which was stirred vigorously for 20 minutes then was extracted with ethyl acetate. The organic phases were combined, dried over magnesium sulphate and evaporated. The residue was chromatographed on silica gel (AnaLogix SF40-80g column), eluting with 80/20 heptane/ethyl acetate.
- 730 mg of tert-butyl 4-(2,4-bisbenzyloxyphenyl)-4-hydroxypiperidine-1-carboxylate was obtained in the form of an oil. Yield = 37%.
- A mixture of 82.3 g (0.168 mmol, 1 eq) of tert-butyl 4-(2,4-bisbenzyloxyphenyl)-4-hydroxypiperidine-1-carboxylate in 620 mL of ethyl acetate and 210 mL of methanol in the presence of 16.4 g of 10% palladium on charcoal was stirred at 55°C under hydrogen at atmospheric pressure for 6 days. The reaction medium was filtered and the filtrate was concentrated and filtered. 38.9 g of tert-butyl 4-(2,4-dihydroxyphenyl)-piperidine-1-carboxylate was obtained in the form of an off-white solid. Yield = 79%.
- 70 g of tert-butyl 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylate was dissolved in 500 mL of ethyl acetate, then 150 mL of a solution of 4M hydrogen chloride in ethyl acetate was added. The reaction mixture was stirred for 2 hours at ambient temperature, then the solid formed was filtered. 36 g of 4-(2,4-dihydroxyphenyl)piperidinium hydrochloride was obtained. Yield = 69%.
- 913 mg (4.79 mmol, 1.1 eq) of alpha-toluenesulphonyl chloride in solution in 5 mL of N,N-dimethylformamide was added dropwise to a solution of 1.0 g (4.35 mmol, 1 eq) of 4-(2,4-dihydroxyphenyl)-piperidinium hydrochloride in 15 mL of N,N-dimethylformamide in the presence of 758 µL (4.35 mmol, 1 eq) of diisopropylethylamine. The reaction medium was stirred at ambient temperature for 4 hours. The reaction medium was treated with water and extracted with ethyl acetate. The organic phases were combined, washed with water, dried over magnesium sulphate and evaporated off. The residue was chromatographed on silica gel eluted with heptane/ethyl acetate (gradient).
- 409 mg of 4-(1-phenylmethanesulphonylpiperidin-4-yl)-benzene-1,3-diol was obtained in the form of a white solid. MP = 207-208°C. Yield = 27%.
- 1 H NMR (DMSO, 400 MHz) : 1.17 (m, 2H); 1.47 (d, J = 12 Hz, 2H); 2.73 (m, 3H); 3.63 (d, J = 12 Hz, 2H); 4.40 (s, 2H); 6.14 (dd, J = 8.4 & 2.4 Hz, 1H) ; 6.26 (d, J = 2.4 Hz, 1H) ; 6.79 (d, J = 7.9 Hz, 1H) ; 7.39 (m, 5H) ; 8.98 (s, 1H) ; 9.17 (s, 1H).
- 13 C NMR (DMSO, 100 MHz) : 31.4, 33.9, 46.3, 54.3, 102.3, 106.0, 121.7, 126.7, 128.0, 128.3, 129.6, 130.9, 155.1, 156.2.
- In a manner analogous to that of Example 1, but using p-toluenesulphonyl chloride in the place of alpha-toluenesulphonyl chloride, 4-[1-(toluene-4-sulphonyl)piperidin-4-yl]benzene-1,3-diol was obtained. MP = 206-207°C.
- 1 H NMR (DMSO, 400 MHz): 1.60 (m, 2H); 1.70 (m, 2H); 2.19 (t, J = 10.9 Hz, 2H); 2.41 (s, 3H); 2.49 (m, 1H); 3.72 (d, J = 11.6 Hz, 1H); 6.12 (dd, J = 8.4 & 2.4 Hz, 1H); 6.22 (d, J = 2.4 Hz, 1H); 6.77 (d, J = 7.9 Hz, 1H); 7.46 (d, J = 8.4 Hz, 1H); 7.63 (d, J = 8.4 Hz, 1H), 8.98 (s, 1H); 9.10 (s, 1H).
- 13 C NMR (DMSO, 100 MHz): 20.99, 30.7, 33.7, 46.8, 102.3, 106.0, 121.5, 126.7, 127.5, 129.7, 132.4, 143.4, 155.2, 156.2.
- In a manner analogous to that of Example 1, but using butylsulphonyl chloride, 4-[1-(butane-1-sulphonyl)-piperidin-4-yl]benzene-1,3-diol was obtained. MP = 182-183°C. Yield = 33%.
- 1 H NMR (DMSO, 400 MHz) : 0.90 (t, J = 7.2 Hz, 3H); 1.17 (m, 2H); 1.75-1.35 (m, 6H); 2.79 (m, 3H); 3.02 (t, J = 7.8 Hz, 2H); 3.66 (d, J = 11.6 Hz, 1H); 6.15 (dd, J = 8.4 & 2.0 Hz, 1H); 6.26 (d, J = 2.0 Hz, 1H); 6.82 (d, J = 7.9 Hz, 1H); 8.98 (s, 1H); 9.18 (s, 1H).
- 13 C NMR (DMSO, 100 MHz) : 13.5, 21.0, 24.7, 31.4, 33.9, 46.1, 47.3, 102.4, 106.0, 121.8, 126.7, 155.2, 156.2.
- The activity of the inhibitors was measured using a lysate of B16F1 cells (murine melanoma line). In the presence of L-tyrosine substrate, the tyrosinase present in these cells catalyses the hydroxylation of L-tyrosine to L-DOPA then oxidation of the L-DOPA to dopaquinone. In the presence of MBTH (3-methyl-2-benzothiazolinone hydrazone), dopaquinone is trapped to form a pink complex which absorbs at 520 nm.
- The B16F1 cells were cultivated in DMEM medium + 10% foetal calf serum + 10-9 M of αMSH for 4 days at 37°C under 7% CO2. They were treated with trypsin, washed with PBS, counted and centrifuged. The pellet was taken up in an amount of 107 cells/mL in lysis buffer (sodium phosphate, 10 mM pH 6.8 -
Igepal 1%) and the suspension was treated with ultrasound for 10 seconds. After centrifuging for 30 minutes at 4000 rpm, the supernatant obtained constituted the cell lysate used as the source of tyrosinase in the enzymatic test. - The tests were carried out in duplicate in 384-well plates with a total volume of 50 µl. Each well contained:
- 40 µl of solution containing 1.25 mM of L-tyrosine, 6.25 µM of L-DOPA (cofactor) and 3.75 mM of MBTH in buffer B (sodium- phosphate 62.25 mM, pH 6.8 - 2.5% dimethylformamide);
- 5 µl of inhibitor diluted in DMSO;
- 5 µl of cell lysate diluted to half strength in Tris HCl buffer, 50 mM, pH 7.5.
- The plate was incubated at 37°C and a spectrographic recording was produced at 520 nm after 6 hours incubation. In order to compensate for any absorption by the products, a corrected absorbance was used (absorbance at time 6 h - absorbance at time zero).
- The inhibitors were dose-response tested in order to calculate the IC50 (dose inhibiting 50% of enzymatic activity).
- A number of internal controls were added in each experiment:
- 100% activity control: the 5 µl of inhibitor was replaced with 5 µl of DMSO;
- 50% activity control: the 5 µl of inhibitor was replaced with 5 µl of phenylthiourea, 300 µM in DMSO;
- 0% activity control: the L-tyrosine substrate was replaced with buffer B.
-
- The inhibition of melanogenesis was measured in MNT1 human melanoma cells using a protocol adapted from Reigner et al, Cell Mol Biol (1999) 45: 969-980. The test was based on the concomitant incorporation of 2 radiolabelled tracers: 14C-thiouracil is incorporated into neosynthesized melanin and reflects melanogenesis, while 3H-leucine is incorporated into proteins and reflects cell viability and, as a result, the toxicity of the test compounds.
- The MNT1 cells were plated into 96-well plates in the presence of the test compounds and radioisotopes. After 24h incubation at 37°C, the cells were washed and the quantity of the 2 radioisotopes was measured. The test compounds were dose-response tested in order to calculate the IC50 inhibition of melanogenesis on the basis of the 14C incorporation which was normalized by the 3H incorporation. A cell toxicity IC50 was also calculated on the basis of the 3H incorporation.
-
- This example illustrates various formulations based on the compounds of the invention.
-
(a) Ointment • compound 20.020 g • isopropyl myristate 81.700 g • fluid vaseline oil 9.100 g • silica ("Aerosil 200") 9.180 g (b) Ointment • compound 20.300 g • white vaseline codex qsp 100 g (c) Non-ionic water-in-oil cream • compound 20.100 g • mixture of emulsified lanolin alcohols, waxes and oils ("anhydrous eucerin") 39.900 g • methyl para-hydroxybenzoate 0.075 g • propyl para-hydroxybenzoate 0.075 g • sterile demineralized water qsp 100 g (d) Lotion • compound 20.100 g • polyethylene glycol (PEG 400) 69.900 g • 95% ethanol 30.000 g (e) Hydrophobic ointment • compound 20.300 g • isopropyl myristate 36.400 g • silicone oil ("Rhodorsil 47V300") 36.400 g • beeswax 13.600 g • silicone oil ("Abil 300.000 cst") qsp 100 g (f) Non-ionic water-in-oil cream • compound 21.000 g • cetyl alcohol 4.000 g • glycerol monostearate 2.500 g • PEG 50 stearate 2.500 g • shea butter 9.200 g • propylene glycol 2.000 g • methyl para-hydroxybenzoate 0.075 g • propyl para-hydroxybenzoate 0.075 g • sterile demineralized water qsp 100 g
m and n may independently take the
as well as salts of these compounds with general formula (I) and their enantiomeric forms.
Claims (9)
- Compounds with the following general formula (I):
R1 represents:• a C1-C8 alkyl radical;• a C3-C8 cycloalkyl radical;• a C4-C10 methylcycloalkyl radical;• an aryl radical;• a substituted aryl radical;• a heteroaryl radical;• a substituted heteroaryl radical;• an aralkyl radical; or• a C1-C5 alkoxy radical;Y represents hydrogen or fluorine; and
m and n may independently take the values 0, 1 or 2;
as well as salts of the compounds with formula (I), and their enantiomeric forms. - Compound according to Claim 1, characterized in that it is in the form of a salt formed with a base selected from organic bases and inorganic bases.
- Compound according to Claim 1 or 2, characterized in that it is in the form of a hydrate or a solvate.
- Compound according to one of Claims 1 to 3, characterized in that:• R1 represents:• a substituted aryl radical;• an aralkyl radical;• a C3-C8 cycloalkyl radical; or• a C4-C10 methylcycloalkyl radical;• Y represents hydrogen or fluorine;• m = 1 and n = 1;as well as salts of said compounds with general formula (I) and their isomeric and enantiomeric forms.
- Compound according to one of Claims 1 to 4, characterized in that it is selected from the group constituted by:1: 4-(1-phenylmethanesulphonylpiperidin-4-yl)-benzene-1,3-diol;2: 4-[1-(toluene-4-sulphonyl)piperidin-4-yl]-benzene-1,3-diol;3: 4-[1-(butane-1-sulphonyl)piperidin-4-yl]-benzene-1,3-diol;4: 4-(1-cyclohexylmethanesulphonylpiperidin-4-yl)-benzene-1,3-diol;5: 4-[1-(2-phenylethanesulphonyl)piperidin-4-yl]-benzene-1,3-diol;6: 1-[4-(2,4-dihydroxyphenyl)piperidine-1-sulphonylmethyl]-7,7-dimethyl-bicyclo[2.2.1]heptan-2-one;7: 4-fluoro-6-[1-(toluene-4-sulphonyl)piperidin-4-yl]benzene-1,3-diol;8: 4-fluoro-6-(1-phenylmethanesulphonylpiperidin-4-yl)benzene-1,3-diol;9: 4-fluoro-6-[1-(2-phenylethanesulphonyl)-piperidin-4-yl]benzene-1,3-diol;10:4-(1-cyclohexylmethanesulphonylpiperidin-4-yl)-6-fluorobenzene-1,3-diol;11:4-[1-(butane-1-sulphonyl)piperidin-4-yl]-6-fluorobenzene-1,3-diol;12:4-[1-(toluene-4-sulphonyl)pyrrolidin-3-yl]-benzene-1,3-diol;13:4-(1-phenylmethanesulphonylpyrrolidin-3-yl)-benzene-1,3-diol;14:4-[1-(2-phenylethanesulphonyl)pyrrolidin-3-yl]benzene-1,3-diol;15:4-fluoro-6-[1-(2-phenylethanesulphonyl)-pyrrolidin-3-yl]benzene-l,3-diol;16:4-(1-cyclohexylmethanesulphonylpyrrolidin-3-yl)benzene-1,3-diol;17:4-[1-(butane-1-sulphonyl)pyrrolidin-3-yl]-benzene-1,3-diol.
- Compound according to any one of Claims 1 to 5, as a drug.
- Compound according to Claim 6, characterized in that said compound has a tyrosinase inhibiting activity.
- Compound as a drug according to Claim 6 or 7, for use in the treatment and/or prevention of pigmentary disorders.
- Compound for use according to Claim 8, characterized in that the pigmentary disorders are selected from melasma, chloasma, lentigines, senile lentigo, irregular hyperpigmentations linked to photo-ageing, freckles, post-inflammatory hyperpigmentations due to abrasion, a burn, a scar, dermatosis, or a contact allergy; naevi, hyperpigmentations with genetic determinism, hyperpigmentations of metabolic or drug origin, melanomas or any other hyperpigmentary lesion.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US28206409P | 2009-12-10 | 2009-12-10 | |
FR0958829A FR2953834B1 (en) | 2009-12-10 | 2009-12-10 | NOVEL 4- (AZACYCLOALKYL) -BENZENE-1,3-DIOL COMPOUNDS AS TYROSINASE INHIBITORS, PROCESS FOR THEIR PREPARATION AND THEIR USE IN HUMAN MEDICINE AND COSMETICS |
PCT/EP2010/069195 WO2011070080A1 (en) | 2009-12-10 | 2010-12-08 | 4- (azacycloalkyl) -benzene-1, 3 -diol derivatives as tyrosinase inhibitors and their synthesis and use thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
EP2509945A1 EP2509945A1 (en) | 2012-10-17 |
EP2509945B1 true EP2509945B1 (en) | 2014-03-05 |
Family
ID=42046368
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP10787772.2A Active EP2509945B1 (en) | 2009-12-10 | 2010-12-08 | 4-(azacycloalkyl)-benzene-1,3-diol derivatives as tyrosinase inhibitors and their synthesis and use thereof |
Country Status (12)
Country | Link |
---|---|
US (1) | US20120323012A1 (en) |
EP (1) | EP2509945B1 (en) |
JP (1) | JP2013513573A (en) |
KR (1) | KR20120112525A (en) |
CN (1) | CN102741228B (en) |
AU (1) | AU2010329896B2 (en) |
CA (1) | CA2782946A1 (en) |
ES (1) | ES2469115T3 (en) |
FR (1) | FR2953834B1 (en) |
MX (1) | MX2012006211A (en) |
RU (1) | RU2012128865A (en) |
WO (1) | WO2011070080A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2016511761A (en) * | 2013-02-14 | 2016-04-21 | ガルデルマ・リサーチ・アンド・デヴェロップメント | Method for synthesizing 4-piperidin-4-yl-benzene-1,3-diol and salts thereof, and novel compound tert-butyl 4- (2,4-dihydroxy-phenyl) -4-hydroxy-piperidine-1-carboxylate |
CR20220236A (en) | 2019-11-28 | 2022-10-03 | Bayer Pharma AG | Substituted aminoquinolones as dgkalpha inhibitors for immune activation |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0651619B2 (en) | 1988-05-09 | 1994-07-06 | 株式会社クラレ | Whitening agent |
FR2704428B1 (en) | 1993-04-29 | 1995-06-09 | Oreal | Use of derivatives of resorcin substituted in position (s) 4, 4 and 5 or 4 and 6 in cosmetic or dermopharmaceutical compositions with depigmenting action. |
BR9803596A (en) | 1997-09-23 | 2000-04-25 | Pfizer Prod Inc | Derivatives of resorcinol. |
MXPA03002080A (en) * | 2000-09-11 | 2003-06-24 | Pfizer Prod Inc | Resorcinol derivatives. |
US6852310B2 (en) | 2002-08-23 | 2005-02-08 | Unilever Home & Personal Care Usa Division Of Conopco, Inc. | Skin lightening agents, compositions and methods |
US6875425B2 (en) * | 2002-12-12 | 2005-04-05 | Unilever Home & Personal Care Usa | Skin lightening agents, compositions and methods |
US7300646B2 (en) | 2004-02-27 | 2007-11-27 | Unilever Home & Personal Care Usa, Division Of Conopco, Inc. | Skin lightening agents, compositions and methods |
US20060210498A1 (en) | 2005-03-18 | 2006-09-21 | Unilever Home & Personal Care Usa, Division Of Conopco, Inc. | Novel resorcinol derivatives for skin |
US20060210497A1 (en) | 2005-03-18 | 2006-09-21 | Unilever Home & Personal Care Usa, Division Of Conopco, Inc. | Novel resorcinol derivatives |
FR2939135B1 (en) * | 2008-12-02 | 2010-12-03 | Galderma Res & Dev | NOVEL 4- (AZACYCLOALKYL) -BENZENE-1,3-DIOL COMPOUNDS AS TYROSINASE INHIBITORS, PROCESS FOR THEIR PREPARATION AND THEIR USE IN HUMAN MEDICINE AND COSMETICS |
-
2009
- 2009-12-10 FR FR0958829A patent/FR2953834B1/en not_active Expired - Fee Related
-
2010
- 2010-12-08 ES ES10787772.2T patent/ES2469115T3/en active Active
- 2010-12-08 EP EP10787772.2A patent/EP2509945B1/en active Active
- 2010-12-08 RU RU2012128865/04A patent/RU2012128865A/en not_active Application Discontinuation
- 2010-12-08 MX MX2012006211A patent/MX2012006211A/en active IP Right Grant
- 2010-12-08 JP JP2012542541A patent/JP2013513573A/en active Pending
- 2010-12-08 CN CN201080063455.8A patent/CN102741228B/en not_active Expired - Fee Related
- 2010-12-08 US US13/514,282 patent/US20120323012A1/en not_active Abandoned
- 2010-12-08 KR KR1020127017698A patent/KR20120112525A/en not_active Application Discontinuation
- 2010-12-08 CA CA2782946A patent/CA2782946A1/en not_active Abandoned
- 2010-12-08 AU AU2010329896A patent/AU2010329896B2/en not_active Expired - Fee Related
- 2010-12-08 WO PCT/EP2010/069195 patent/WO2011070080A1/en active Application Filing
Also Published As
Publication number | Publication date |
---|---|
RU2012128865A (en) | 2014-01-20 |
US20120323012A1 (en) | 2012-12-20 |
FR2953834B1 (en) | 2012-01-13 |
CA2782946A1 (en) | 2011-06-16 |
CN102741228A (en) | 2012-10-17 |
ES2469115T3 (en) | 2014-06-17 |
AU2010329896A1 (en) | 2012-07-12 |
AU2010329896B2 (en) | 2015-03-26 |
JP2013513573A (en) | 2013-04-22 |
CN102741228B (en) | 2014-09-24 |
EP2509945A1 (en) | 2012-10-17 |
WO2011070080A1 (en) | 2011-06-16 |
MX2012006211A (en) | 2012-06-19 |
KR20120112525A (en) | 2012-10-11 |
FR2953834A1 (en) | 2011-06-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2373620B1 (en) | Novel 4-(azacycloalkyl)benzene-1,3-diol compounds as tyrosinase inhibitors, process for the preparation thereof and use thereof in human medicine and in cosmetics | |
EP2373310B1 (en) | Novel 4-(heterocycloalkyl)benzene-1,3-diol compounds as tyrosinase inhibitors, process for the preparation thereof and use thereof in human medicine and also in cosmetics | |
EP2509945B1 (en) | 4-(azacycloalkyl)-benzene-1,3-diol derivatives as tyrosinase inhibitors and their synthesis and use thereof | |
US8119674B2 (en) | 4-phenylimidazole-2-thione tyrosinase inhibitors and pharmaceutical/cosmetic applications thereof | |
US20100160401A1 (en) | 4-phenylimidazole-2-thione tyrosinase inhibitors and treatment or prevention of pigmentary disorders therewith |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20120710 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
AX | Request for extension of the european patent |
Extension state: BA ME |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
INTG | Intention to grant announced |
Effective date: 20130919 |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
AX | Request for extension of the european patent |
Extension state: BA ME |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: REF Ref document number: 654778 Country of ref document: AT Kind code of ref document: T Effective date: 20140315 |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R096 Ref document number: 602010014060 Country of ref document: DE Effective date: 20140417 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2469115 Country of ref document: ES Kind code of ref document: T3 Effective date: 20140617 |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: MK05 Ref document number: 654778 Country of ref document: AT Kind code of ref document: T Effective date: 20140305 |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: VDEP Effective date: 20140305 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 Ref country code: NO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140605 |
|
REG | Reference to a national code |
Ref country code: LT Ref legal event code: MG4D |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: AT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 Ref country code: SE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 Ref country code: CY Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 Ref country code: FI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: HR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 Ref country code: LV Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 Ref country code: RS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: EE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 Ref country code: CZ Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 Ref country code: BG Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140605 Ref country code: NL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 Ref country code: BE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 Ref country code: IS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140705 Ref country code: RO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: PL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 Ref country code: SK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R097 Ref document number: 602010014060 Country of ref document: DE |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: PT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140707 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DE Payment date: 20141202 Year of fee payment: 5 Ref country code: GB Payment date: 20141203 Year of fee payment: 5 Ref country code: ES Payment date: 20141111 Year of fee payment: 5 |
|
26N | No opposition filed |
Effective date: 20141208 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 20141208 Year of fee payment: 5 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R097 Ref document number: 602010014060 Country of ref document: DE Effective date: 20141208 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: IT Payment date: 20141126 Year of fee payment: 5 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20141208 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20141231 Ref country code: IE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20141208 Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20141231 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SM Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MC Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140606 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R119 Ref document number: 602010014060 Country of ref document: DE |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 Ref country code: TR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 Ref country code: HU Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO Effective date: 20101208 |
|
GBPC | Gb: european patent ceased through non-payment of renewal fee |
Effective date: 20151208 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: ST Effective date: 20160831 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20160701 Ref country code: GB Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20151208 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20151231 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20151208 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FD2A Effective date: 20170126 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: ES Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20151209 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: AL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140305 |